This application addresses broad Challenge Area (11): Regenerative Medicine and specific Challenge Topic, 11-HL-101: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Sudden cardiac death (SCD) due to myocardial infarction (MI) is the most common cause of mortality from heart disease. Current therapies such as implantable cardioverter defibrillators and antiarrhythmic drugs are palliative and often provoke life-threatening cardiac arrhythmias. Radiofrequency (RF) catheter ablation can cure arrhythmias associated with MI;however, many patients are not suitable and the recurrence rate is high. Consequently, SCD remains a major unresolved public health problem. In many patients with chronically healed MI, SCD is due to reentrant ventricular tachycardia (VT) caused by abnormal electrical impulse conduction in the vicinity of scar tissue. Therapy that directly targets this abnormal electrical substrate may decrease the incidence of VT. For example, RF ablation targets the substrate by permanently destroying tissue critical to the reentrant circuit. However, this procedure expands necrosis beyond the preexisting disease-induced scar, which may explain why this therapy is not always successful. We propose a novel paradigm to address this challenge: rather than destroying more tissue and creating additional areas of abnormal conduction, a more efficacious approach to cure VT is to restore normal conduction to critical regions of the reentrant circuit using targeted cell therapy. Cell therapy appears as a promising treatment for myocardial repair associated with acute MI. Importantly, studies from our laboratory using mesenchymal stem cell (MSC) therapy have shown that electrical viability in scar tissue can be partially restored due to, in part, a direct effect of the cells administered. Additionally, indirect (paracrine) effects, such as stem cell recruitment, can be induced by the release of cellular signals such as SDF-1. However, the chemical signals that promote such paracrine effects are absent in chronically healed MI. This and poor retention of cells that are directly injected create several barriers to the survival, engraftment, and ultimately the restoration of electrical viability of scar tissue in the setting of healed MI. We hypothesize that targeted cell therapy can be used to restore impulse propagation in pathways critical to the reentrant circuit and prevent VT associated with chronic MI;however, robust stem cell engraftment and recruitment will be required. Our objectives are to determine if the engraftment and recruitment of stem cells in chronic MI can be enhanced using hydrogels and paracrine factors. We will also determine if stem cell therapy can abolish slow conduction and reduce susceptibility to VT in a clinically relevant model of chronic MI/VT. The long term goal of this proposal is to create a novel and efficacious paradigm for treating VT that can be easily transitioned to clinical trials and, eventually, transform the standard of care for patients with MI at risk for SCD. PUBLIC HEALTH RELEVANCE: Several hundred thousand people suffer sudden cardiac death (SCD) each year in the United States. Current treatment with implantable cardioverter defibrillators, antiarrhythmic drug therapy, and radio frequency catheter ablation are ineffective at treating the underlying pathophysiological causes of SCD. Consequently, SCD remains a major unresolved public health problem. This proposal puts forth a novel method using targeted cellular therapy to restore normal function and, thus, cure many patients at risk for SCD. 1